Mechanisms of injury-induced calcium entry into peripheral nerve myelinated axons: role of reverse sodium-calcium exchange

J Neurochem. 1996 Feb;66(2):493-500. doi: 10.1046/j.1471-4159.1996.66020493.x.


To investigate the route of axonal Ca2+ entry during anoxia, electron probe x-ray microanalysis was used to measure elemental composition of anoxic tibial nerve myelinated axons after in vitro experimental procedures that modify transaxolemmal Na+ and Ca2+ movements. Perfusion of nerve segments with zero-Na+/Li(+)-substituted medium and Na+ channel blockade by tetrodotoxin (1 microM) prevented anoxia-induced increases in Na and Ca concentrations of axoplasm and mitochondria. Incubation with a zero-Ca2+/EGTA perfusate impeded axonal and mitochondrial Ca accumulation during anoxia but did not affect characteristic Na and K responses. Inhibition of Na(+)-Ca2+ exchange with bepridil (50 microM) reduced significantly the Ca content of anoxic axons although mitochondrial Ca remained at anoxic levels. Nifedipine (10 microM), an L-type Ca2+ channel blocker, did not alter anoxia-induced changes in axonal Na, Ca, and K. Exposure of normoxic control nerves to tetrodotoxin, bepridil, or nifedipine did not affect axonal elemental composition, whereas both zero-Ca2+ and zero-Na+ solutions altered normal elemental content characteristically and significantly. The findings of this study suggest that during anoxia, Na+ enters axons via voltage-gated Na+ channels and that subsequent increases in axoplasmic Na+ are coupled functionally to extraaxonal Ca2+ import. Intracellular Na(+)-dependent, extraaxonal Ca2+ entry is consistent with reverse operation of the axolemmal Na(+)-Ca2+ exchanger, and we suggest that this mode of Ca2+ influx plays a general role in peripheral nerve axon injury.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Bepridil / pharmacology
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / physiology*
  • Cell Hypoxia
  • In Vitro Techniques
  • Male
  • Nerve Fibers, Myelinated / metabolism*
  • Oxygen / metabolism
  • Perfusion
  • Rats
  • Rats, Sprague-Dawley
  • Reference Values
  • Sodium / pharmacology
  • Sodium Channel Blockers
  • Sodium-Calcium Exchanger
  • Tibial Nerve


  • Calcium Channel Blockers
  • Carrier Proteins
  • Sodium Channel Blockers
  • Sodium-Calcium Exchanger
  • Bepridil
  • Sodium
  • Oxygen
  • Calcium